The focus of this application is on abnormalities of TDP-43, a protein that underlies a number of neurodegenerative diseases (frontotemporal lobar dementia [FTLD], Parkinson's disease [PD], and amyotrophic lateral sclerosis [ALS]). In 2006, ubiquinated cytoplasmic inclusions in neurons in FTLD were found to contain abnormally phosphorylated fragments of aggregated TDP-43, a DNA-binding protein normally nuclear in location. Remarkably, TDP-43 inclusions are seen in all patients with sporadic ALS, the majority of patients with familial ALS (FALS), and in all patients with sporadic and familial FTLD with ubiquitin-positive, tau-negative inclusions with or without ALS. TDP-43 mutations have recently been identified in FALS patients, indicating the clear direct involvement of mutant (MT) TDP-43 in ALS. The mechanism underlying the toxicity of TDP-43 remains unclear;however, the presence of cytoplasmic aggregates suggests that misfolding of this protein is important in the pathogenesis of ALS. These aggregates may sequester TDP-43 binding-proteins important to the viability of the motor neuron (MN). In this application we plan to use phage display libraries to: (1) identify and characterize peptides that bind TDP- 43 and predict the cellular interacting proteins;(2) identify and characterize single chain fragments of variable region antibodies (scFvs) that can be used to clarify the function of TDP-43 and may have therapeutic potential. PUBLIC HEALTH RELEVANCE: Amyotrophic lateral sclerosis (ALS) is a desperate disease in which there is no cure and no effective treatment. This application involves identifying peptide ligands and generating antibodies that bind a protein that appears to be key to the pathogenesis of ALS as well as other neurodegenerative processes. The peptide ligands may be used to predict the cellular interacting proteins and the antibodies may clarify the function of the protein. Together, this work may provide insight into why mutations of this protein cause ALS, and potentially provide a direction for treatment of sporadic and inherited ALS (as well as other neurodegenerative diseases).